Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We propose to create novel autism model mouse lines. We will produce both conditional and reversible knockouts as well as global, complete and isoform specific knockouts of autism candidate genes to mimic human autism mutations. Our progress to date is substantial in that we have now demonstrated of several mutant mouse models related to autism, thereby establishing these lines for our studies and for the general neuroscience community. We now propose to expand these novel autism model mouse lines and perform initial molecular, biochemical, electrophysiologic and behavioral characterization. In particular, we will measure behaviors corresponding to each of the three core symptom domains in autism spectrum disorder in these mouse lines. The result will be novel genetic model mouse lines of autism, behavioral relevance of the model to autism, and initial studies on brain function using electrophysiology to understand effects on cortical synapses. PUBLIC HEALTH RELEVANCE: Our goal is to better understand genetic causes of human autism and to use animal models of such causes to identify treatments. This 5-year R01 proposal capitalizes on our significant progress in creating animal models of autism and will allow us to rapidly advance this field. The marriage of our understanding of brain pathology with behavioral abnormalities in these mice will lead to testable hypotheses regarding pharmacologic treatment of autism symptoms in the model and ultimately in autistic patients.